Regulatory Decision Summary for Enhertu

This Supplemental New Drug Submission (SNDS) was submitted to seek market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Enhertu (trastuzumab deruxtecan) filed by AstraZeneca Canada Inc. for the treatment of adult patients with locally advanced or metastatic gastric or gastroesophageal cancer.

After evaluation of the submitted data package, Health Canada authorized with conditions Enhertu for the following indication:

Enhertu as monotherapy is indicated for the treatment of adult patients with unresectable, locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.

See Enhertu Product Monograph for other authorized indications.

The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

Authorization was based on the results from two Phase 2 multi-centre, open-label trials: DESTINY-Gastric01 and DESTINY-Gastric02.

The DESTINY-Gastric01 trial enrolled 126 adult patients from Japan and South Korea with HER2-positive unresectable locally advanced or metastatic gastric or gastroesophageal junction (GEJ) cancer who had previously been treated and progressed on at least two prior regimens including trastuzumab, a fluoropyrimidine and a platinum agent. Patients were randomized (2:1) to receive either Enhertu 6.4 mg/kg once every three weeks or physician’s choice (either irinotecan or paclitaxel as per local guidelines) until disease progression, death, withdrawal of consent or unacceptable toxicity. The demographics and baseline disease characteristics were similar between the two arms with the majority of patients being male and having gastric adenocarcinoma. The primary endpoint was unconfirmed objective response rate (ORR) assessed by independent central review while overall survival (OS) was the key secondary endpoint. At primary analysis, the unconfirmed ORR was 48.4% in the Enhertu arm compared with 12.9% in the control arm. For OS, the hazard ratio was 0.59 with the median survival in the Enhertu arm being 12.5 months compared to 8.4 months in the control arm. These clinically meaningful and statistically significant results were supported by the other secondary endpoints.

The DESTINY-Gastric 02 trial is a single arm study that was conducted in the United States and Europe and enrolled 79 adult patients with HER2-positive gastric or GEJ adenocarcinoma who had previously been treated and progressed on one prior trastuzumab-based regimen in. The majority of patients were male and had GEJ adenocarcinoma. Patients were treated with Enhertu 6.4 mg/kg once every three weeks until disease progression, death, withdrawal of consent or unacceptable toxicity. At the primary analysis, the confirmed ORR was 38.0%.

Together, the efficacy results from both trials are considered promising evidence of clinical effectiveness.

The most common adverse reactions reported in HER2-postivie gastric/GEJ cancer patients treated with Enhertu were nausea, decreased appetite, fatigue, neutropenia, anemia, thrombocytopenia, vomiting, diarrhea, leukopenia, constipation, alopecia, and pyrexia. The most common serious adverse reactions were decreased appetite, interstitial lung disease (ILD), pneumonia, nausea, vomiting, dehydration, anemia, diarrhea, abdominal pain, and pyrexia. Fatalities due to adverse reactions were due to ILD and pneumonia. These safety findings are consistent with those from previous studies with Enhertu which are adequately described in the Product Monograph.

Overall, the benefit-risk profile is positive for the use of Enhertu (trastuzumab deruxtecan for injection) for the treatment of adult patients with HER2-positive gastric and GEJ adenocarcinoma that is unresectable, locally advanced or metastatic and who have progressed on a trastuzumab-based regimen.

The recommended dose of Enhertu for adult patients with unresectable, locally advanced or metastatic HER2-positive gastric/GEJ cancer who have been previously treated with a trastuzumab-based regimen is 6.4 mg/kg every three weeks. For further details about Enhertu, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.

As a condition of authorization, confirmation of clinical benefit is required and the sponsor is conducting an ongoing randomized, controlled Phase 3 study, DESTINY-Gastric04. Health Canada granted this application advanced consideration under the NOC/c policy. For more information on the conditions issued, please refer to the Notice of Compliance with conditions (NOC/c) Website.

An updated Risk Management Plan (RMP) for Enhertu was reviewed by Health Canada and considered acceptable.

Risks have been communicated in the approved Product Monograph and will continue to be monitored post market as outlined in the Risk Management Plan, with routine and non-routine pharmacovigilance activities.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.